Vitiligo is a chronic depigmenting disorder that is manifested by the sudden appearance of white patches on skin. Depigmentation of entire skin in vitiligo follows a variable and often unpredictable course. While the prevalence of vitiligo varies from 0.5-2% in the world, the disease is of major concern in India, where it is considered as a major social stigma. The disfigurement caused by the disease has profound effects on the quality of life of the individual, with subjects feeling distressed and isolated. Depigmentation in vitiligo is considered a consequence of melanocyte disappearance from the basal layer of skin. However, very rarely non-functional melanocytes may be observed in depigmented skin of some vitiligo patients. The exact cause of the disease is an enigma as the mechanisms underlying melanocyte disappearance are still not known, but several hypotheses have been proposed trying to explain the pathogenesis of vitiligo. The co-occurrence of vitiligo and autoimmune disorders such as thyroid disease, pernicious anaemia, Addison's disease, alopecia areata, systemic lupus erythromatosus, and inflammatory bowel disease, has lead researchers to suspect autoimmune patho-mechanisms. Further evidence for autoimmune aetiology comes from the presence of serum autoantibodies against melanocyte antigens such as the tyrosinase family of enzymes, melanoma antigen recognized by T cells 1 (MART-1), premelanosome protein (PMEL17) and melanocortin-1 receptor in some subjects.
The discovery of melanocyte-specific T cell infiltrates in the advancing margins of lesions and in the peripheral blood compartment along with the ability of these T cells to express the required cytotoxic molecules in the vicinity of melanocytes to cause their destruction has given further credence to the theory that an autoimmune response is central to the pathogenesis of vitiligo.
Several studies have now shown these effector CD8+ T cells to be associated with substantial melanocyte loss in depigmented lesions. The dysfunction of T regulatory cells in the peripheral compartment may be another one of the possible reasons why this aberrant immune response is not controlled. Further, recent studies have shown significant association of HLA alleles and haplotypes. The current treatment regime for vitiligo is thus, focussed on ameliorating the excessive immune activity. These intervention strategies include usage of corticosteroids, calcineurin inhibitors, PUVA (Psoralen plus UVA) and UVB therapy.
Calreticulin (CRT) is a ubiquitous Endoplasmic Reticulum resident calcium-binding protein that primarily functions as a chaperone. Cell surface CRT (Ecto CRT) presentation is proposed to trigger a series of events that lead to activation of effector CD8+ T cells, resulting in immunogeniuc cell death (ICD). This activation pathway is defined during treatment-elicited immunogenic cell death of cancers, where conventional anticancer chemotherapies and radiotherapies activate dendritic cells via CRT pathway, triggering effector T cells. In vitiligo, melanocytes disappear from the lesional skin. Substantial number of melanocyte cell death occurs through CD8+ effector T cells. ICD of melanocytes could be the potential mechanism leading to the activation of CD8+ effector T cells, resulting in melanocyte loss in vitiligo. A recent study has reported a positive relationship between soluble CRT expression in blood plasma and the duration of disease and lesion area in vitiligo patients. CRT overexpression was correlated with the degree of destruction of melanocytes, suggesting that CRT could be a regulator of oxidative stressinduced apoptosis in melanocytes (Y Zhang et al, Journal of Investigative Dermatology, 2014).
U.S. Pat. No. 8,927,736 disclosed a method for preparing a 1,2,3-triazole compound comprising contacting an organic azide with a 2-substituted-1-haloalkyne, in the presence of a copper catalyst and a copper-coordinating ligand (preferably a tertiary amine) in a liquid reaction medium, thereby forming a 1,4,5-substituted-1,2,3-triazole compound including a halo substituent at the 5-position of the triazole, the organic portion of the organic azide at the 1-position of the triazole, and the substituent of the 1-iodoalkyne at the 4-position of the triazole.
Article titled “Synthesis of 1H-1,2,3-triazole derivatives by the cyclization of aryl azides with 2-benzothiazolylacetonone, 1,3-benzo-thiazol-2-ylacetonitrile, and (4-aryl-1,3-thiazol-2-yl)acetonitriles” by N T Pokhodylo et al. published in Chemistry of Heterocyclic Compounds, 2009, Volume 45, Issue 4, pp 483-488 reports cyclization of aryl azides with 2-benzothiazolylacetone, 1,3-benzothiazol-2-ylacetonitrile, and (4-aryl-1,3-thiazol-2-yl)acetonitriles in methanol in the presence of sodium methylate gives high yields of new products, 2-(5-methyl(amino)-1-aryl-1H-1,2,3-triazol-4-yl)-1,3-benzothiazoles and 1-aryl-(4-aryl-1,3-thiazol-2-yl)-1H-1,2,3-triazole-5-amines.
Article titled “Synthesis of 2-Azido-1,3-thiazoles as 1,2,3-Triazole Precursors” by N T Pokhodylo et al. published in Synthetic Communications, 2010, Volume 40, Issue 3, pp 391-399 reports diazotization of 2-aminothiazoles and reaction with sodium azide, the derivatives of 2-azidothiazole. 2-Azidothiazole derivatives were studied in the base-catalysed condensation reactions with activated methylenic compounds to yield new 1-(1,3-thiazol-2-yl)-1H-1,2,3-triazole-4-carboxylic acids.
Vitiligo is considered to be due to autoimmune destruction of melanocytes. The methods and the drugs available in the market for treatment of vitiligo are targeted to suppress immune activity in subjects. However, these treatments do not target the mechanisms that sustain autoimmune reactions, and hence provide only temporary and symptomatic relief.
Therefore, there is need to design synthetic compounds that can suppress the immunogenic cell death (ICD) pathway and exposure of surface calreticulin in melanocytes which can provide new treatment options for stalling vitiligo spread which the prior art has failed to attain. Accordingly, the present inventors propose 1,2,3 triazole-thiazole compounds that can stall or prevent the spread of depigmentation in Vitiligo by suppressing immunogenic cell death of melanocytes and preventing localization of calreticulin to the cell surface of melanocytes.